RESUMO
Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for null mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.
Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Proteínas de Drosophila/genética , Medo/fisiologia , Proteínas do Tecido Nervoso/genética , Vestíbulo do Labirinto/patologia , Tonsila do Cerebelo/metabolismo , Animais , Sequência de Bases , Comportamento Animal/fisiologia , Drosophila melanogaster/genética , Feminino , Deleção de Genes , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Análise de Sequência de DNA , Fatores Sexuais , Sono/genética , Sono/fisiologia , Núcleo Supraquiasmático/metabolismo , Testes de Função Vestibular , Vestíbulo do Labirinto/fisiologiaRESUMO
Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation and the Eya1(BOR) model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggests selective advantage. A congenic Mvb1(CAST) allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.
Assuntos
Alelos , Proteínas de Ligação a DNA/genética , Retrovirus Endógenos/genética , Sequência de Aminoácidos , Animais , Teste de Complementação Genética , Humanos , Íntrons , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Mutagênese Insercional , Proteínas Repressoras , Homologia de Sequência de Aminoácidos , Fatores de Transcrição , TransgenesRESUMO
The rich behavioral repertoire of animals is encoded in the CNS as a set of motorneuron activation patterns, also called 'motor synergies'. However, the neurons that orchestrate these motor programs as well as their cellular properties and connectivity are poorly understood. Here we identify a population of molecularly defined motor synergy encoder (MSE) neurons in the mouse spinal cord that may represent a central node in neural pathways for voluntary and reflexive movement. This population receives direct inputs from the motor cortex and sensory pathways and, in turn, has monosynaptic outputs to spinal motorneurons. Optical stimulation of MSE neurons drove reliable patterns of activity in multiple motor groups, and we found that the evoked motor patterns varied on the basis of the rostrocaudal location of the stimulated MSE. We speculate that these neurons comprise a cellular network for encoding coordinated motor output programs.